1. Field of the Invention
The present invention relates to a process for the preparation of pharmaceutically acceptable salts of (R,S)-S-adenosyl-L-methionine (hereinafter referred to as (R,S)-SAMe). (“(R,S)-S-adenosyl-L-methionine” means a mixture of (R)-S-adenosyl-L-methionine and (S)-S-adenosyl-L-methionine.)
In particular, the invention relates to a process for the preparation of pharmaceutically acceptable salts of (R,S)-SAMe, wherein the salified (R)-(+)-S-adenosyl-L-methionine diastereoisomer (hereinafter referred to as (R)-(+)-SAMe) is produced in amounts lower than or equal to 3% with respect to the salified (S)-(+)-S-adenosyl-L-methionine diastereoisomer (hereinafter referred to as (S)-(+)-SAMe.
2. Description of the Background
As it is known, (R,S)-SAMe is a physiological methyl donor involved in enzymatic transmethylation reactions, that is present in all living organisms and has therapeutical effects on chronic hepatic diseases, adiposis, lipaemia, atherosclerosis and it is desirable, therefore, to produce it in high amounts.
It is also known, (J. W. Comforth, J.A.C.S., 1977, 99, 7292-7300; Stolowitz et al., J.A.C.S., 1981, 103, 6015-6019) that the products containing (R,S)-SAMe consist of a mixture of two diastereoisomers: (R)-(+)-SAMe and (S)-(+)-SAMe, having the following structural formulae: 
Moreover, it was demonstrated (De La Haba et al., J.A.C.S., 1959, 81, 3975-3980) that only one of the two diastereoisomers, i.e. (S)-(+)-SAMe, is enzymatically active for the transmethylation and spontaneously racemises, thereby giving rise to the formation of the inactive diastereoisomer (R)-(+)-SAMe in a percentage equal to about 20% (Wu et al., Biochemistry 1983, 22, 2828-2832).
The Applicant, in fact, has noted that in all the commercially available-products based on (R,S)-SAMe, the inactive diastereoisomer (R)-(+)-SAMe is present in percentages equal to at least 20%; it was also noted that said percentages increase in time even up to 40% and more.
This observation clearly confirms that the diasteroisomer mixture is unstable in time, which, on the other side, had already been noted in relation with the product in solution (G. L. Creason et al., Phytochemistry, vol. 24, N. 6, 1151-1155, 1985; H. C. Uzar, Liebigs Ann. Chem. 1989, 607-610).
The demand for (R,S)-SAMe derivatives wherein the percentage of the active (S)-(+)-SAMe diastereoisomer is clearly higher with respect to the inactive (R)-(+)-SAMe isomer and wherein said percentage turns out to be stable in time, is particularly felt in the field.
It was also found that there is an obstacle to the use of (R,S)-SAMe and the pharmaceutically acceptable salts thereof at the industrial level because of their thermal instability, even at room temperature, and of the complexity of the preparation and purification processes thereof.
Several processes for the purification of (R,S)-SAMe and for the production of the pharmaceutically acceptable salts thereof are known.
However, the known purification processes, besides providing the use of strong acid resins (JP 13680/1971) or chelate-type resins (JP 20998/1978) or particular and expensive reactants, such as picric or picolinic acid (U.S. Pat. Nos. 3,707,536 and 3,954,726), bring anyhow to the partial racemisation of the sulphur chiral center of (R,S)-SAMe and, therefore, lead to final products containing the inactive diastereoisomer in amounts higher than 20%.
Purification processes that use weak acid resins are also known (JP 14299/1981, FR-A-2531714, EP-A-0141914), which allow, however, to obtain just a partial separation of (SS, RS)-SAMe and, therefore, an insufficient purity degree for pharmaceutical purposes.
Even if the realization of some of the above-identified processes enables to obtain a higher purity, the partial racemization implies, at any event, that at least 20% of the inactive diastereoisomer should be present; in some cases moreover (FR-2531714), in order to extract the product from the cells, there is provided the use of potassium bicarbonate, with subsequent precipitation of potassium perchlorate, which brings about problems firstly in the separation and then in the disposal of the product. In EP-A-0141914, the lysis of the cells of the yeast containing (R,S)-SAMe is carried out in the presence of an organic solvent (for example, ethyl acetate, acetone, etc.) by using, moreover, chromatographic columns based on 100-200 mesh resins, with high investment and maintaining costs. The use of solvents for the extraction of (R,S)-SAMe necessarily implies the employment of antideflagrant plants and a recovery, distillation and solvent recovery systems, besides the necessary drying of the exhausted mycelium, in order to avoid that it is discharged with the residual solvent, all these factors clearly bringing about additional investment and operation costs.